Adjuvant Chemotherapy for Upper Tract Urothelial Cancer


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ADJUVANT CHEMOTHERAPY achieved robust improvements in disease-free survival and metastasis-free survival compared with surveillance in the phase III POUT study of patients with upper tract urothelial cancer.1 Further, there was an early trend toward improved overall survival with adjuvant chemotherapy.

Alison J. Birtle, MD

Alison J. Birtle, MD

“Adjuvant chemotherapy improves disease-free survival and metastasis-free survival. It is feasible in a group of patients, with the majority over age 60. Adjuvant chemotherapy should be considered a new standard of care,” stated lead author Alison J. Birtle, MD, a clinical oncologist and Honorary Senior Lecturer at Rosemere Cancer Centre, Lancashire Teaching Hospitals, Preston, United Kingdom.

Session moderator Nicholas J. Van As, MD, of The Royal Marsden Hospital, London, commended Dr. Birtle and coauthors: “This was a challenging study to do, with outstanding results.”

Nicholas J. Van As, MD

Nicholas J. Van As, MD

Dr. Birtle said: “It is a triumph getting behind a trial with a low-incidence tumor. Upper tract urothelial cancer is a relatively rare disease. It is safe to say it is more lethal than muscle-invasive bladder cancer, [but] it has been neglected.”

Standard treatment for upper tract urothelial cancer is radical nephro-urectomy followed by surveillance, with chemotherapy given when needed. “There is a paucity of data to guide us as to whether to use adjuvant chemotherapy. Small studies of systemic chemotherapy show a tantalizing hint of benefit in disease-free survival and overall survival, so we set out to explore this in a larger study,” Dr. Birtle told listeners.

Some oncologists in the United States favor neoadjuvant therapy for upper tract urothelial cancer based on randomized controlled trials showing an overall survival benefit with that approach in urothelial carcinoma of the bladder. “Because, in historical series, at least 10% of patients thought to have upper tract urothelial cancer turn out not to have cancer when the surgical specimen is biopsied, and another 10% to 15% have low-grade disease, there is a risk of overtreatment with neoadjuvant chemotherapy, which has also been proposed for this disease,” she explained.

Study Details

THE POUT STUDY enrolled 26,261 patients with histologically confirmed stage pT2–T4, N0–N3 upper tract urothelial cancer following radical nephro-ureteretomy and removal of any obvious nodal disease and with a negative postoperative CT scan. Within 90 days postsurgery, patients were randomized 1:1 to receive 4 cycles of gemcitabine-based chemotherapy or surveillance. The choice of chemotherapy partner (cisplatin or carboplatin) depended on glomerular filtration rate alone; those with a glomerular filtration rate > 50 mL/min were given cisplatin, and if the glomerular filtration rate was 30 to 49 mL/min, they were given carboplatin. Patients who were deemed unfit for cisplatin based on other comorbidities were not allowed to be entered into the trial. All patients received supportive care.

A RELATIVELY UNCOMMON DISEASE

  • In the phase III POUT trial, adjuvant chemotherapy significantly improved disease-free survival and metastasis-free survival compared with surveillance and chemotherapy given at relapse in patients with upper tract urothelial cancer.
  • A trend toward improved overall survival was observed, but longer follow-up is needed.

The planned sample size was 338 patients, but after 5 years, 261 patients were recruited from 57 centers in the United Kingdom. One patient was excluded, and Dr. Birtle reported on an intent-to-treat population of 260. Baseline characteristics were well balanced between the two study arms. Two-thirds of patients were male, 80% were over age 60, and 5% were over age 80.

Two-thirds of the patients had locally advanced disease, 90% were node-negative, and 90% were surgical margin–negative. Two-thirds were eligible for cisplatin. Compliance was considered good: About 70% received all four planned cycles of chemotherapy.

For the primary endpoint of 3-year disease-free survival rate, chemotherapy had a strong benefit: 71% in the chemotherapy group vs 54% in the surveillance group, representing a 51% improvement that was statistically significant (P = .001). Chemotherapy was significantly superior to surveillance in subgroups of nodal involvement, planned type of chemotherapy, microscopic margin, and disease stage (with a similar hazard ratio for benefit seen across all subgroups).

Metastasis-free survival at 2 years also favored adjuvant chemotherapy: 74% for chemotherapy vs 60% for surveillance, a 51% benefit (P < .001).

“There is a hint of an overall survival benefit, with curves diverging early, and a hazard ratio of 0.55,” Dr. Birtle said. Longer follow-up is needed to assess this endpoint. The study was stopped early because the efficacy favored the chemotherapy arm, she told the audience.

Toxicity data were available for 257 patients. Grade 3 or higher toxicities were reported in 53.2% of the chemotherapy recipients and 13.5% of the surveillance group. The most frequent grade 3 or higher toxicities reported in the chemotherapy group were as follows: neutropenia in 24.3% of those treated with gemcitabine/ cisplatin and 37.3% of those given gemcitabine/carboplatin; nausea in 2.9% and 7.8%, respectively; vomiting in 1.4% and 9.8%; and febrile neutropenia in 5.7% and 7.8%.

No neutropenic deaths were reported. There was 1 death in the chemotherapy group due to a gastric bleed at 1 year posttreatment that was not treatment-related.

Multidisciplinary Effort

IN A SEPARATE interview, Dr. Birtle explained that POUT was a multidisciplinary effort. Her group conducted surveys of patients with upper tract urothelial cancer based on interviews and developed language—called Top Tips—that encouraged study participation. Top Tips can be used to recruit patients for other trials, she explained. She attributed the good concordance and acceptance of study drugs to the use of this language when recruiting patients, framing participation in a randomized trial in a manner that did not deter them.

Another strategy Dr. Birtle and her colleagues used was “buddying” patients in the trial with other patients who had been treated with chemotherapy earlier. These discussions eased patients’ fears. “This patient-centered trial overcame barriers to enrollment,” she said.

“This study should change standard practice. Disease-free survival and metastasis-free survival were better than we expected. We need to build on this study with international collaboration and have larger studies powered for survival,” Dr. Birtle stated. ■

DISCLOSURE: Dr. Birtle has had a consulting or advisory role with Astellas Medivation, AstraZeneca, Bayer Schering Pharma, Janssen Oncology, Roche, and Sanofi and has received honoraria from Janssen-Cilag. Dr. Van As reported no conflicts of interest.

REFERENCE

1. Birtle AJ, Chester JD, Jones R, et al: Results of POUT: A phase III randomized trial of prospective chemotherapy versus surveillance in upper tract urothelial cancer. 2018 Genitourinary Cancers Symposium. Abstract 407. Presented February 9, 2018.


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EXPERT POINT OF VIEW: Timothy Gilligan, MD

“POUT IS an impressive study, given that the authors were able to complete a trial in this relatively rare cancer. We still need overall survival data to determine the role of adjuvant chemotherapy for upper tract urothelial cancer. We need to know if it makes people live longer or have a better...

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